The Genetic and Neurobiological Studies section of the Huntington's Disease Research Center examines patterns of disease expression with the goal of identifying disease modifying mechanisms which may be invoked for treatment of the illness. The four proposed projects are; 1. Variation in clinical expression. We propose investigations in three areas to evaluate the effects of modifying factors upon disease expression: (a) We propose to examine the relationship of repeat size to disease expression including the onset age and rate of progression. (b) We propose to study factors contributing to the variation in disease expression other than the trinucleotide repeat. (c) We propose to examine factors associated with large intergenerational expansion of the expanded CAG repeat. By defining these modifiers, more accurate estimates of the expected disease course and onset can be made, and will permit assessment of change from the expected disease course in clinical trials. 2. CAG repeat expansion from intermediate to clinical range. We reported the overlap between the intermediate (32 to 38 repeats) and the clinical range of 37 repeats in families with de novo expressions of HD. These studies suggest that repeat size atone is not sufficient for HD expression. We propose to study patterns of repeat stability in our existing sample of de novo expression families as well as newly identified families. We will compare the stability of this repeat among progeny of male versus female members of the family in multiple generations for biologic mechanisms influencing repeat stability. The genetic risks associated with intermediate repeats are unknown and this has created ambiguities in genetic testing. 3. Brain Studies. Our past brain studies have generated two competing hypotheses; (a) either the HD gene interferes with early cortical and subcortical development, or (b) the gene's effects accrue gradually in mid-life in a normally developed central nervous system (CNS). Our recent studies of brain specimens of HD gene carriers dying before onset of disease found increased oligodendrocyte densities in the tail of the caudate nucleus suggesting early CNS development abnormalities. We propose to expand the number of presymptomatic HD cases studied and to examine regions afflicted only in later stages of disease as well as regions of white matter. We hypothesize that cell density abnormalities will be observed throughout he presymptomatic HD brain. 4). Collection of fetal tissues of HD gene carriers. We propose to collect fetal brain, testes and ovaries, and other tissues to be made available to HD center and other investigators. One of the largest predictive and prenatal testing programs in the nation is affiliated with our HD center and we estimate 2 to 5 prenatal tests per year in this program. Until now no systematic program for collection of fetal tissues from across the nation has existed. We propose therefore to establish a network among HD testing facilities nationwide to coordinate the collection of fetal tissues.